Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1

Kleanthi Chalkiadaki; Mehdi Hooshmandi; Gilliard Lach; Elpida Statoulla; Konstanze Simbriger; Ines S Amorim; Stella Kouloulia; Maria Zafeiri; Panagiotis Pothos; Éric Bonneil; Ilse Gantois; Jelena Popic; Sung-Hoon Kim; Calvin Wong; Ruifeng Cao; Noboru H Komiyama; Yaser Atlasi; Seyed Mehdi Jafarnejad; Arkady Khoutorsky; Christos G Gkogkas

doi:10.1093/brain/awac398

Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1

Kleanthi Chalkiadaki, Mehdi Hooshmandi, Gilliard Lach, Elpida Statoulla, Konstanze Simbriger, Ines S Amorim, Stella Kouloulia, Maria Zafeiri, Panagiotis Pothos, Éric Bonneil, Ilse Gantois, Jelena Popic, Sung-Hoon Kim, Calvin Wong, Ruifeng Cao, Noboru H Komiyama, Yaser Atlasi, Seyed Mehdi Jafarnejad, Arkady Khoutorsky, Christos G Gkogkas

Research output: Contribution to journal › Article › peer-review

Abstract

MAPK (mitogen-activated protein kinase) interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterised substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that whereas deletion of Mnk1/2 (Mnk DKO) impairs synaptic plasticity and memory in mice, ablation of phosho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 since Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk DKO mice. Knock-down of Syngap1 reversed memory deficits in Mnk DKO mice, and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.

Original language	English
Journal	Brain
Early online date	31 Oct 2022
DOIs	https://doi.org/10.1093/brain/awac398
Publication status	E-pub ahead of print - 31 Oct 2022

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Chalkiadaki, K., Hooshmandi, M., Lach, G., Statoulla, E., Simbriger, K., Amorim, I. S., Kouloulia, S., Zafeiri, M., Pothos, P., Bonneil, É., Gantois, I., Popic, J., Kim, S-H., Wong, C., Cao, R., Komiyama, N. H., Atlasi, Y., Jafarnejad, S. M., Khoutorsky, A., & Gkogkas, C. G. (2022). Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1. Brain. https://doi.org/10.1093/brain/awac398

@article{da33797d3f4642d2889fd484bcfadf7d,

title = "Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1",

abstract = "MAPK (mitogen-activated protein kinase) interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterised substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that whereas deletion of Mnk1/2 (Mnk DKO) impairs synaptic plasticity and memory in mice, ablation of phosho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 since Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk DKO mice. Knock-down of Syngap1 reversed memory deficits in Mnk DKO mice, and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.",

author = "Kleanthi Chalkiadaki and Mehdi Hooshmandi and Gilliard Lach and Elpida Statoulla and Konstanze Simbriger and Amorim, {Ines S} and Stella Kouloulia and Maria Zafeiri and Panagiotis Pothos and {\'E}ric Bonneil and Ilse Gantois and Jelena Popic and Sung-Hoon Kim and Calvin Wong and Ruifeng Cao and Komiyama, {Noboru H} and Yaser Atlasi and Jafarnejad, {Seyed Mehdi} and Arkady Khoutorsky and Gkogkas, {Christos G}",

note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2022",

month = oct,

day = "31",

doi = "10.1093/brain/awac398",

language = "English",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

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Chalkiadaki, K, Hooshmandi, M, Lach, G, Statoulla, E, Simbriger, K, Amorim, IS, Kouloulia, S, Zafeiri, M, Pothos, P, Bonneil, É, Gantois, I, Popic, J, Kim, S-H, Wong, C, Cao, R, Komiyama, NH, Atlasi, Y, Jafarnejad, SM, Khoutorsky, A & Gkogkas, CG 2022, 'Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1', Brain. https://doi.org/10.1093/brain/awac398

TY - JOUR

T1 - Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1

AU - Chalkiadaki, Kleanthi

AU - Hooshmandi, Mehdi

AU - Lach, Gilliard

AU - Statoulla, Elpida

AU - Simbriger, Konstanze

AU - Amorim, Ines S

AU - Kouloulia, Stella

AU - Zafeiri, Maria

AU - Pothos, Panagiotis

AU - Bonneil, Éric

AU - Gantois, Ilse

AU - Popic, Jelena

AU - Kim, Sung-Hoon

AU - Wong, Calvin

AU - Cao, Ruifeng

AU - Komiyama, Noboru H

AU - Atlasi, Yaser

AU - Jafarnejad, Seyed Mehdi

AU - Khoutorsky, Arkady

AU - Gkogkas, Christos G

PY - 2022/10/31

Y1 - 2022/10/31

N2 - MAPK (mitogen-activated protein kinase) interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterised substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that whereas deletion of Mnk1/2 (Mnk DKO) impairs synaptic plasticity and memory in mice, ablation of phosho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 since Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk DKO mice. Knock-down of Syngap1 reversed memory deficits in Mnk DKO mice, and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.

AB - MAPK (mitogen-activated protein kinase) interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterised substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that whereas deletion of Mnk1/2 (Mnk DKO) impairs synaptic plasticity and memory in mice, ablation of phosho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 since Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk DKO mice. Knock-down of Syngap1 reversed memory deficits in Mnk DKO mice, and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.

U2 - 10.1093/brain/awac398

DO - 10.1093/brain/awac398

M3 - Article

C2 - 36315645

JO - Brain

JF - Brain

SN - 0006-8950

ER -

Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1

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